Moss-Derived Human Recombinant GAA Provides an Optimized Enzyme Uptake in Differentiated Human Muscle Cells of Pompe Disease
| Autor: | Andreas Schaaf, Nicola Krieghoff, Birgit Berg, Benedikt Schoser, Paulina Dabrowska-Schlepp, Peter Meinke, Stefan Hintze, S Limmer, Andreas Busch |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mannose lcsh:Chemistry Myoblasts chemistry.chemical_compound Mice 0302 clinical medicine Glycogen storage disease type II Myocyte lcsh:QH301-705.5 Spectroscopy Cells Cultured Glycogen Myogenesis Chemistry Glycogen Storage Disease Type II Pompe disease General Medicine Enzyme replacement therapy Recombinant Proteins Computer Science Applications medicine.anatomical_structure medicine.drug medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Bryophyta Catalysis Article Inorganic Chemistry 03 medical and health sciences Internal medicine medicine Animals Humans Enzyme Replacement Therapy Physical and Theoretical Chemistry Molecular Biology Alglucosidase alfa Muscle Cells Organic Chemistry Skeletal muscle nutritional and metabolic diseases alpha-Glucosidases moss-GAA medicine.disease 030104 developmental biology Endocrinology lcsh:Biology (General) lcsh:QD1-999 Energy Metabolism 030217 neurology & neurosurgery Biomarkers |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 21, Iss 2642, p 2642 (2020) Volume 21 Issue 7 |
| ISSN: | 1422-0067 |
| Popis: | Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The result of the GAA deficiency is a ubiquitous lysosomal and non-lysosomal accumulation of glycogen. The most affected tissues are heart, skeletal muscle, liver, and the nervous system. Replacement therapy with the currently approved enzyme relies on M6P-mediated endocytosis. However, therapeutic outcomes still leave room for improvement, especially with regard to skeletal muscles. We tested the uptake, activity, and effect on glucose metabolism of a non-phosphorylated recombinant human GAA produced in moss (moss-GAA). Three variants of moss-GAA differing in glycosylation pattern have been analyzed: two with terminal mannose residues in a paucimannosidic (Man3) or high-mannose (Man 5) configuration and one with terminal N-acetylglucosamine residues (GnGn). Compared to alglucosidase alfa the moss-GAA GnGn variant showed increased uptake in differentiated myotubes. Moreover, incubation of immortalized muscle cells of Gaa&minus /&minus mice with moss-GAA GnGn led to similarly efficient clearance of accumulated glycogen as with alglucosidase alfa. These initial data suggest that M6P-residues might not always be necessary for the cellular uptake in enzyme replacement therapy (ERT) and indicate the potential of moss-GAA GnGn as novel alternative drug for targeting skeletal muscle in Pompe patients. |
| Databáze: | OpenAIRE |
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